Understanding the translation regulation of Fragile X Mental Retardation Protein (FMRP) through its interaction with the ribosome

Abstract

Fragile X Syndrome (FXS) is a trinucleotide repeats expansion disorder of the FMR1 gene resulting in intellectual disability. The silencing of the gene due to the expansion of CGG repeat in its 5'UTR results in the loss of the encoded protein Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is nucleo-cytoplasmic located and structurally comprises of protein-interacting, RNA-binding and intrinsically disordered domains, which contribute to its versatile role in a range of biological processes such as chromatin remodeling, ion channel stability, RNA transport and ribosome heterogeneity. Most importantly, FMRP regulates the translation of mRNAs essential for synaptic development and plasticity making it critical for neuronal function and development. The function of FMRP is complex and the contribution of FMRP to FXS pathology is mostly investigated in the absence of the protein. Studying the localization and role of individual domains is beneficial in understanding FMRP-mediated regulation of protein synthesis. Hence I systematically investigated the contribution of FMRP and its individual domains in the dynamic processes of ribosome binding, mRNP granule formation, and microtubule association. I also emphasize the role of phosphorylation of FMRP at Serine 500 in these processes. Additionally, I elucidate the functional consequences of pathogenic point mutations on regulatory mechanisms controlled by FMRP. Lastly, my work also describes a novel role for nuclear FMRP and how its interaction with nuclear small RNA can regulate the ribosome and thus protein synthesis. This is important to understand FMRP domains and their role in coordinating the mechanisms leading to translation regulation.